Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated neurons in humans and animal models

Shinsuke Kato, Yusuke Saeki, Masashi Aoki, Makiko Nagai, Aya Ishigaki, Yasuto Itoyama, Masako Kato, Kohtaro Asayama, Akira Awaya, Asao Hirano, Eisaku Ohama

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H2O2), and H2O2 is then converted into harmless water (H2O) and oxygen (O2) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala→Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.

Original languageEnglish (US)
Pages (from-to)149-158
Number of pages10
JournalActa Neuropathologica
Volume107
Issue number2
DOIs
StatePublished - Feb 2004

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Oxidation-Reduction
Animal Models
Neurons
Glutathione
Lewy Bodies
Hyalin
Transgenic Rats
Motor Neurons
Superoxide Dismutase-1
Codon
Reactive Oxygen Species
Peroxiredoxins
Antibodies
Superoxides
Base Pairing
Hydrogen Peroxide
Spinal Cord
Antioxidants
Oxygen
Rabbits

Keywords

  • Familial amyotrophic lateral sclerosis
  • Glutathione peroxidase 1
  • Peroxiredoxin 2
  • Redox system
  • Superoxide dismutase 1

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated neurons in humans and animal models. / Kato, Shinsuke; Saeki, Yusuke; Aoki, Masashi; Nagai, Makiko; Ishigaki, Aya; Itoyama, Yasuto; Kato, Masako; Asayama, Kohtaro; Awaya, Akira; Hirano, Asao; Ohama, Eisaku.

In: Acta Neuropathologica, Vol. 107, No. 2, 02.2004, p. 149-158.

Research output: Contribution to journalArticle

Kato, S, Saeki, Y, Aoki, M, Nagai, M, Ishigaki, A, Itoyama, Y, Kato, M, Asayama, K, Awaya, A, Hirano, A & Ohama, E 2004, 'Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated neurons in humans and animal models', Acta Neuropathologica, vol. 107, no. 2, pp. 149-158. https://doi.org/10.1007/s00401-003-0791-1
Kato, Shinsuke ; Saeki, Yusuke ; Aoki, Masashi ; Nagai, Makiko ; Ishigaki, Aya ; Itoyama, Yasuto ; Kato, Masako ; Asayama, Kohtaro ; Awaya, Akira ; Hirano, Asao ; Ohama, Eisaku. / Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated neurons in humans and animal models. In: Acta Neuropathologica. 2004 ; Vol. 107, No. 2. pp. 149-158.
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